ProjectSummary Agoalofbasicmentalhealthresearchistounderstandthemolecular,cellularandcircuitlevelsubstratesthat contributetoneuropsychiatricdisorders.Thegoalofthisprojectistobetterunderstandtheprinciples underlyingcircuitdysfunctionassociatedwithcognitiveandsocialimpairmentscommontothesedisorders.A promisingapproachtobetterunderstandthesesubstratesistoperformin-depthstudiesinanimalmodelswith highconstructandfacevalidities.DenovopathogenicSYNGAP1mutationsleadingtohaploinsufficiency causeonethemostcommongeneticallydefinedandnon-inheritedformsofintellectualdisability(ID)with autismspectrumdisorder(ASD;?termedMRD5;?OMIN#612621).Studiessupportedbythefirstbudgetperiod identifiedSyngap1heterozygousKOmiceasanoutstandinggeneticmodelofASDwithID.Usingthismodel, wediscoveredadevelopmentalsensitiveperiodofSyngap1functionthatpromotestheproperfunctionof corticalnetworks.Theneurobiologicalstudieswepublishedinthelastperiodweresignificantbecausethey identifiedthedevelopmentaltimingofdendriteandspinematurationselectivitywithinforebrainexcitatory neuronsasacriticalsubstratethatshapesbrainfunctionrelevanttocognitiveandsocialdevelopment. Forthiscompetitiverenewal,wewillbuildonourdiscoveriesinthefirstbudgetperiodbystudyingthekey substratesofcircuitdysfunctionintheSyngap1modelbyprobinghowthisgeneregulatescorticalsensory processingrelevanttocognitionandlearning.Thisapproachissignificantbecausesensoryimpairmentsare extremelycommoninASD/IDandtheseimpairmentsinfluencebehavioraladaptations,includinglearning. Syngap1patientsexpresssensoryabnormalitiesrelatedtotouchandpain.However,thecircuitabnormalities thatunderliesensorydysfunctionareunclear.Thus,ourapproachisinnovativebecausestudieswillbe performedinthemousesomatosensorycortex,whichwillenablepowerfulinvivoexperimentsthatarecapable ofdirectlylinkingcellular-andcircuit-levelfunctionalimpairmentstosensory-basedlearningandbehavioral abnormalities.ThefirstAimwillinvestigatethecellularmechanismsunderlyingimpairedsomatosensorycortex networkfunctioncausedbypathogenicSyngap1mutations,withanemphasisonhownetwork-levelE/I imbalancesemergewithincorticalcircuitsthatdirectlyencodesensoryrepresentations.Researchproposedin thesecondAimwilldeterminethecellularmechanismsthatcontributetosensory-drivenlearningimpairments inSyngap1mice.Theimpactofthesestudiesisthattheyareexpectedtoadvanceourunderstandinghow corticalcircuitdysfunctionleadstobehavioralimpairmentsassociatedwithASD/ID.